: Many biomedical applications require direct contact between the cells and non-biological materials. For example, medical implants inserted into the patient?s body have intimate contact with adjacent cells and tissues. Synthetic materials ?show? only their surfaces to the biological environment. These surfaces are recognized by cells through their chemical composition and their physical properties. Surface chemistry has been studied extensively and many surface functionalization strategies have been developed to promote cell adhesion and integration. The importance of physical properties in modulating cellular behavior, such as surface topography and material rigidity are increasingly recognized. In particular, studies show that surface topography in the scale of tens of nanometers to a few micrometers significantly affect cell adhesion and tissue integration. As topographic features are stable over long-term and easier to control, they offer unique advantages for modulating cell responses for tissue engineering. However, the grant challenge is how to optimize surface topology to achieve a desired function among a high-dimensional space of topological features. To address this challenge, it is imperative to ask the fundamental question ?how do cells detect its environmental topology??. Despite a large body of observations, little is known about the origin or underlying mechanisms of the effect of topographical cues on cell behavior. This proposal aims to answer the fundamental question by proposing and testing a new hypothesis, the curvature hypothesis, based on very recent studies in the PI?s lab. A comprehensive research program will be built to validate the curvature hypothesis by understanding how positive and negative membrane curvatures differentially regulate the intracellular signaling, confirming that membrane curvature is a critical player in topography-induced cell adhesion and stem cell differentiation, and visualizing membrane deformations on a variety of complex surface topography. These studies will not only contribute to mechanistic understandings of the interaction between living cells and synthetic materials, but also accelerate the effort to design material surfaces for desired applications.